tbuckley/cabot-search huggingface dataset:
CNSC-09. CHI3L1 IS A MOLECULAR MARKER FOR GLIOBLASTOMA NETWORK CONNECTIVITY AND FUNCTIONALLY ORCHESTRATES TUMOR MICROTUBE FORMATION
Authors: Dirk Hoffmann, Ling Hai, Robin Wagener, David Hausmann, Daniel Domínguez Azorín, Ruifan Xie, Magnus-Carsten Huppertz, Julien Hiblot, Philipp Sievers, Jakob Ito, Sophie Weil, Gina Cebulla, Henriette Mandelbaum, Erik Jung, Alexandros Kourtesakis, Kati Ernst, Denise Reibold, Uwe Warnken, Varun Venkataramani, Rainer Will, Mario Suva, Christel Herold-Mende, Felix Sahm, Frank Winkler, Matthias Schlesner, Wolfgang Wick, Tobias Kessler
Journal: Neuro-Oncology (2023)

Abstract Chitinase 3-like 1 (CHI3L1) is a secreted glycoprotein and its RNA expression elevated in glioblastoma (GB) compared to other tumor types and related normal tissues. Furthermore, transcript levels in GB dictate aggressiveness through modulating stemness, proliferation and tumor microenvironment. This ultimately influences patient survival. We here provide evidence that the pathogenic relevance of CHI3L1 expression is associated with the extent of tumor microtubes (TMs) - ultralong membrane tubes that connect GB cells (GBCs) to a network with considerable relevance for tumor progression and therapy resistance. Single cell RNA profiling of xenografted GBCs with different degrees of morphological and functional TMs identified CHI3L1 as a prognostic marker for TM network extent. We demonstrate that both RNA and protein expression levels are suitable markers in preclinical in vitro systems modeling TM connectivity as well as in clinical specimens. Genetic perturbation of CHI3L1 influenced GBC network integration, caused a shift of the dominant cell state and altered the phosphorylation status of the TM-driver GAP43. Pharmacological blocking of CHI3L1 with an antibody reduced TM networks, thus providing a handle for future clinical translation. Together, these data identify a functional and upstream role of CHI3L1 in governing tumor cell connectivity, CHI3L1 RNA and protein expression as a novel way to determine overall GBC connectivity for future trials, and finally a new therapeutic target for tumor network-disrupting strategies.
TMIC-40. BIOPHYSICAL ANALYSIS OF GLIOBLASTOMA CORE AND RIM REVEAL UNIQUE MECHANICAL AND ULTRASTRUCTURAL SIGNATURES
Authors: Bradley Mahaffey, Zachary Fowler, Zoe Lung, Vivien Dang, Hermann Frieboes, Brian Williams, Joseph Chen
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is a highly aggressive and invasive brain cancer, carrying a median survival of 15 months. This poor prognosis is due, in part, to its resistance to therapy through tumor adaptations mediated by the tumor microenvironment (TME). Efforts to describe the tumor-protective cues in the TME may aid in the development of strategies to combat resistance. Emerging work has indicated that GBM biophysical properties are significant modulators of tumor progression; however, these parameters are poorly described. Here, we investigate the mechanical, extracellular matrix (ECM), and ultrastructural characteristics of tumors in patient matched GBM core and rim tissue. Using atomic force microscopy, immunohistochemistry, and scanning electron microscopy techniques, we find that GBM core is abnormally stiff and dense with large amounts of ECM, while the rim is softer and more porous. The GBM core is uniquely rich in hyaluronic acid and Tenascin-C, ECM proteins known to correlate with tumor stiffness and tumor supportive function. Additionally, dense matrix along with increased levels of hyaluronic acid and Tenascin-C correlate with decreased progression free survival. These data suggest that the stiff core provides increased pro-malignant mechanotransductive cues while the rim presents more permissive routes for GBM invasion. These results reveal a biophysical basis for tumor progression and provides a novel framework for diagnostic strategies and therapeutic intervention.
TMIC-50. SIGLEC-15 IS A NEW MYELOID CHECKPOINT IN GBM, WHOSE SUPPRESSION LEADS TO EXTREMELY DURABLE RESPONSES WITH ONCOLYTIC THERAPY
Authors: Ashwani Kesarwani, Amanda De Andrade Costa, Tong Hu, Jeremy Rich, Albert Kim, Pei-Yong Shi, Michael S Diamond, Milan Chheda
Journal: Neuro-Oncology (2023)

Abstract Zika virus (ZIKV) significantly increases survival in multiple syngeneic glioma mouse models; like other oncolytic therapies, it generates a potent, anti-tumor CD8+ T-cell response. Post-ZIKV, we observe a 32-fold increase in myeloid cells in the tumor microenvironment. Siglec-15 is a newly identified myeloid immune checkpoint in cancer, which suppresses T-cell activation; an antibody targeting Siglec-15 is currently in clinical trial for lung cancer. Using immunostaining, for the first time, we report Siglec-15 is expressed on myeloid cells in human GBM specimens. In syngeneic murine models, anti-Siglec-15 alone does not improve survival. However, in combination with ZIKV, anti-Siglec-15 significantly improves survival in the CT2A, SB28, and GL261 models. For example, in the CT2A model, the combination increased long-term survivors (at least 90 days) to 60%, compared to 20% with ZIKV alone and 0% with no treatment. To further confirm the role of Siglec-15, we used Siglec-15 knockout (KO) mice and observed 70% long-term survivor rate in Siglec-15 KO mice treated with ZIKV, compared to 40% in wild-type mice (B/6) with ZIKV. ZIKV treatment in Siglec-15 KO mice led to activation of CD8 T-cells and increased expression of cytotoxic molecules granzyme B and perforin, indicating enhanced anti-tumor activity. Additionally, we detected high levels IFN-gamma and TNF-alpha, further supporting the anti-tumor response. We further improved efficacy by targeting PD-1. This combination resulted in 90% long-term survivors. Moreover, in a model for recurrence, upon contralateral rechallenge with CT2A in long-term survivors, we observed long-term memory T-cell responses, with increased numbers of CD8+ T-cells displaying effector and resident memory cell phenotypes, compared to age-matched controls. We obtained similar results with immune-resistant SB28 model. This work suggests that oncolytic therapy combined with blocking myeloid checkpoint Siglec-15, using an agent already in humans, and blocking CD8+ T cell checkpoint with anti-PD1, is worthy of study in humans.
SURG-11. RISKS AND BENEFITS OF REPEATED RESECTION FOR GLIOBLASTOMA: A SINGLE INSTITUTION REVIEW OF CHARACTERISTICS AND OUTCOMES OF RESECTION OF RECURRENT GLIOBLASTOMA
Authors: Erin D'Agostino, Isidora Beach, Brandon Liebelt, Alissa Thomas
Journal: Neuro-Oncology (2023)

Abstract Maximal safe resection is standard for newly diagnosed glioblastoma, but for recurrent glioblastoma the value of resection is less clear. We performed a retrospective, single-institution analysis of sequential patients undergoing re-resection for recurrent glioblastoma and analyzed pre-operative risk factors, progression free and overall survival from time of re-resection to death or last follow-up (PFS/OS), and complication rates. Between 2017 and 2022, 38 patients underwent re-resection of glioblastoma (defined by 2016 WHO criteria, 86.8% IDH wild type) and were followed for an average of 157 weeks (range 17-553). The cohort had a mean age of 59.4 years (range 39-87), was 55% male, and included 68.4% MGMT unmethylated tumors. Preoperatively, median Karnofsky Performance Score (KPS) was 80 (range 50-100), and median modified frailty index (mFI-5) was 0 (range 0-4). Re-resection occurred an average of 55.3 weeks after initial resection (SD 59.6, range 5-314), 25.0 weeks after chemotherapy (SD 51.8), and 39.9 weeks after radiation (SD 45.1). Mean OS after re-resection was 67.4 weeks (SD 91.5, range 1-505 weeks), median 59.5 weeks. Average PFS was 24.5 weeks (SD 25.3, range 1-139). The complication rate was 34.2% (n = 15), including 6 patients (15.8%) with a wound infection and 5 (13.1%) with symptomatic hemorrhage. 12 (31.6%) patients had a new neurologic deficit. Postoperative KPS was lower than preoperative KPS (p = .002). Patients with &amp;lt;20 weeks between surgeries, mFI &amp;gt;1, or KPS &amp;lt;80 had higher rates of complications (respectively p = .04, p = .03, p = .03). Patients with mFI &amp;gt;1 or KPS &amp;lt;70 were more likely to die within 30-days of surgery (respectively p = .014; p = .018). Re-resection demonstrated a survival benefit, especially for patients younger than 65 with a mFI of &amp;lt; 2. Though complications were common, post-operative complications were not associated with a shorter overall survival. Consideration for age, frailty, KPS, and timing of surgery may guide selection of patients for re-resection.
MODL-04. ESTABLISHMENT OF TUMOR MICROENVIRONMENT-PRESERVING ORGANOID MODEL FROM PATIENTS WITH INTRACRANIAL MENINGIOMA
Authors: Stephen Ahn
Journal: Neuro-Oncology (2023)

Abstract Although meningioma is the most common primary brain tumor, treatments depend only on the surgery and radiotherapy, and recurrent meningiomas have no standard therapeutic options due to a lack of clinically relevant research models. Current meningioma cell lines or organoids cannot reflect biological features of patients’ tumors since they undergo transformation along culture and consist of only tumor cells without microenvironment. Here, we firstly established patient-derived meningioma organoids (MNOs) preserving diverse cell types of tumor microenvironment, including endothelial cells and macrophage/microglia cells. Exclusion of the enzymatic dissociation-reaggregation steps endowed MNOs with original histology and tumor microenvironment. In addition, we used liquid media culture system instead of embedding into Matrigel, thus easy-to-handle, cost-efficient, and time-saving. MNOs maintained their functionality and morphology after long-term culture ( &amp;gt; 9 wk) and repeated cryopreserving-recovery cycles. The similarity between MNOs and their corresponding parental tumors were confirmed by both immunohistochemistry and whole-exome sequencing. As a representative application, we utilized MNOs in drug screening, and mifepristone, an antagonist of progesterone receptor, showed prominent antitumor efficacy in respect to viability, invasiveness, and protein expression. Taken together, our MNO model overcame limitations of previous meningioma models and showed superiority in terms of resemblance with parental tumors. Thus, we expect that our model can facilitate translational research of identifying and selecting drugs for meningioma in the era of precision medicine.
TMIC-48. SYNAPTIC PROTEINS BASSOON, DLG4, DLG1, MAGI2, SHANK1, AND HOMER1 IN GLIOMA
Authors: Marco Timmer, Nina Lauer, Saskia Kuhl, Roland Goldbrunner
Journal: Neuro-Oncology (2023)

Abstract To thrive, glioma cells exploit pathways that are active in normal CNS cells, as well as in normal neurotransmitter signaling. In healthy excitatory synapses the postsynaptic submembrane space consists of multiprotein complexes called the postsynaptic density (PSD). The PSD is responsible for the structural organization, the functioning, and the regulation of neuronal signaling. The five MAGUK Proteins DLG4, DLG1, Magi2, Shank1, and Homer1 are part of the healthy PSD complex and play a crucial role not only in NMDA and AMPA receptor signaling. Investigating the role of these MAGUK proteins in glioma biology could bring further insight into which principal neurobiological features, including organization in communicating networks, are recapitulated by tumor cells of different stages in gliomas. qPCR was used to determine expression levels of DLG4, DLG1, Magi2, Shank1, and Homer1 in 7 different glioma groups (GII, GIII, primary GBM before and after chemotherapy, secondary glioblastoma recurrence with and without chemotherapy). Western Blot was done for DLG4, DLG1, and Homer1. Immunohistochemical staining of frozen sections, paraffin sections and in vitro cells was performed. The expression levels of DLG4, DLG1, Magi2, Shank1, and Homer1 were reduced especially in high grade glioma compared to control tissue. A tendency of decreasing protein levels with increasing malignancy is visible for the majority of proteins. In cell culture all proteins were also present. siRNA experiments are ongoing. The presence of these synaptic proteins in glioma tissue and moreover also primary cell culture could indicate a role in tumor biology and the connection of glioma cells with neuronal tissue.
RADT-23. STEREOTACTIC RADIOSURGERY FOR CYSTIC VESTIBULAR SCHWANNOMA - A SYSTEMATIC REVIEW
Authors: Lisette Torres, Mahlet Mekonnen, Anna Furton, Aryan Pandey, Sanah Vohra, Isaac Yang
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Cystic vestibular schwannoma, also historically known as cystic acoustic neuroma, is a benign intracranial tumor that can form between the pons and the cerebellum in an area known as the cerebellopontine angle. These brain tumors can be treated with radiotherapy, surgical resection, or radiosurgery. However, there is no consensus on which treatment modality is the most effective with minimal to no complications. METHODS A comprehensive review of clinical articles reporting stereotactic radiosurgery treatment for cystic vestibular schwannoma was performed. PubMed, Web of Science, Cochrane, Scopus, and Embase were independently queried and the PRISMA guidelines were followed throughout the screening process. We identified high-quality studies representing data from 186 patients. We extracted patient demographics, tumor characteristics, type of stereotactic radiosurgery, dosage, tumor control rate, and follow-up time. All the available data points were used to evaluate the effect of stereotactic radiosurgery on tumor control rate for cystic vestibular schwannoma. RESULTS A total of 186 patients underwent stereotactic radiosurgery with Gamma Knife (n = 178) and CyberKnife (n = 8). The average tumor volume was 6.47 cm3 (range 4.82 – 8.4 cm3, SD ± 1.8). The average marginal and maximum doses were 12.8 Gy (12.5 -13 Gy, SD ± 0.25) and 24.9 Gy (23.8 - 26 Gy, SD ± 1.10), respectively. The average follow-up time was 63.5 months (53.5 – 74 months, SD ± 10.2). Following stereotactic radiosurgery treatment for cystic vestibular schwannoma across all studies, almost 92% of patients had tumor control at follow-up, (95%-CI: 91.4 - 91.6). CONCLUSIONS Our systematic review revealed that stereotactic radiosurgery can provide adequate tumor control for cystic vestibular schwannoma. Therefore, stereotactic radiosurgery is an effective treatment choice in patients with cystic vestibular schwannoma.
EXTH-45. DEVELOPMENT OF COMBINATION THERAPIES OF KRASG12C INHIBITOR ADAGRASIB IN PRECLINICAL MODELS OF BRAIN METASTASIS
Authors: Consuelo Torrini, Christian Migliarese, Elizabeth Summers, Fatma Turna Demir, Nazanin Ijad, Naema Nayyar, Erika Yamazawa, Magali De Sauvage, Priscilla Brastianos, Hiroaki Wakimoto
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The highly selective KRASG12C inhibitor adagrasib (MRTX849) is FDA-approved for KRASG12C+ advanced non-small cell lung cancer (NSCLC). We recently provided preclinical evidence of MRTX849 brain penetration and activity, allowing MRTX849 inclusion in a national genomically-guided multicenter clinical trial (NCT03994796) for patients with brain metastasis (BM). However, multiple genetic alterations such as CDKN2A/B deletions, a common driver of NSCLC BM, can limit MRTX849 efficacy. Furthermore, although MRTX849 can sensitize extracranial tumors to immune checkpoint inhibitors (ICI), its intracranial immune benefit is unknown. Our objective was to improve MRTX849 monotherapy, evaluating combination therapies with CDK4/6 inhibitor abemaciclib or anti-PD-1 in preclinical models of BM. METHODS We tested in vitro sensitivity of MRTX849 and abemaciclib, using KRASG12C+, CDKN2A-deleted human lung cancer cell lines SW1573 and H2122. The efficacy of a 5-week treatment of MRTX849 and abemaciclib was evaluated in an intracranial NSCLC BM model in nude mice. Additionally, we utilized a syngeneic murine KrasG12C colorectal cancer BM model (CT26G12C) to test different MRTX849 dosages and assess its therapeutic effects in combination with anti-PD-1 antibody. RESULTS MRTX849 and abemaciclib demonstrated mild synergy in reducing cell viability in vitro. Combination treatment of MRTX849 and abemaciclib significantly improved both survival and intracranial tumor control relative to controls in SW1573 NSCLC BM model. In a syngeneic colorectal BM model, we identified benefit of a 2-week MRTX849 single treatment at 100 mg/kg (BID) in controlling brain tumor growth. In a dual subcutaneous intracranial BM model with CT26G12C, MRTX849 alone and combination therapy mediated complete regression of extracranial tumors. Although monotherapies reduced intracranial tumor growth, MRTX849 combination with anti-PD-1 resulted in a greater benefit. Both MRTX849 monotherapy and the combination therapy extended animal survival. CONCLUSIONS MRTX849 combination therapies with abemaciclib or anti-PD-1 demonstrate intracranial activity, inhibiting BM progression and prolonging survival, in preclinical models of KRASG12C+ BM.
NIMG-73. RADIOGRAPHIC CHANGES AFTER RADIATION THERAPY IN SUBTOTALLY RESECTED ATYPICAL MENINGIOMAS
Authors: Eunji Yim, Peter Pan, Jana Ivanidze, Gloria Chiang, Susan Pannullo, Jonathan Knisely, Andrew Brandmaier, Howard Fine, Rohan Ramakrishna, Theodore Schwartz, Philip Stieg, Benjamin Liechty, David Pisapia, Rajiv Magge
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Adjuvant radiotherapy (RT) has been shown to improve outcomes after subtotal resection (STR) of atypical meningioma, but little is known about how tumors evolve on magnetic resonance imaging (MRI) and whether this correlates with RT response. METHODS We retrospectively identified histologically confirmed cases of WHO Grade II atypical meningioma at a large academic institution from 2004-2020 who underwent subtotal resection and received radiation. Clinicodemographic, surgical, RT, and histopathologic data were collected, as well as clinical outcomes, with a median follow-up time of 69 months (IQR 61). Patients were stratified by external beam RT (EBRT) and stereotactic radiosurgery (SRS). Radiographic data included tumor location, cerebral edema, susceptibility changes, leptomeningeal enhancement, calcification, necrosis, and time to recurrence. Progression was defined by radiology report. RESULTS Of 31 patients with STR for newly diagnosed atypical meningioma, 65% (20 of 31) received RT and 11 of 20 (55%) received EBRT while nine received SRS. Of the convexity/parasagittal meningiomas (N=10), 40% demonstrated venous sinus invasion. 65% (N=13) of cases were treated upfront; the other seven progressed at a median 9.4 months before undergoing RT. Post-RT, 74% decreased in size (N=5) or stabilized (N=9); imaging was not available for one case. Recurrence after RT was observed in five cases. 11 cases developed restricted diffusion at median onset of 24.9 months; 7 developed adjacent leptomeningeal enhancement at median onset of 14.7 months, of which 86% (6 of 7) received SRS. Other patterns included adjacent nodular (N=3) and linear (N=2) enhancement, and adjacent confluent T2 signal (N=4); these could potentially represent radiation-related changes. Only one case developed calcification after 70 months. CONCLUSIONS Atypical meningiomas exhibit variable patterns of evolution after RT which may predict treatment outcomes. Multivariate analysis is planned to correlate radiographic changes with pathology characteristics, RT modality, and time to recurrence.
QOL-29. ILLNESS UNDERSTANDING AND RELIGIOUSNESS IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: John Fortunato, Leah Walsh, Laura Polacek, Katherine Panageas, Anne Reiner, Tobias Walbert, Alissa Thomas, Justin Buthorn, Allison Sigler, Holly Prigerson, Allison Applebaum, Eli Diamond
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is an aggressive neurologic malignancy with invariably poor prognosis. However, there is evidence that patients with GBM often have unrealistic perceptions of their prognosis. Strong religious beliefs have been shown to be associated with limited illness understanding (IU) in patients with advanced cancer, but IU and religiousness have not been investigated in patients with GBM. METHODS Patients enrolled in a prospective multi-center study of recurrent GBM (Coping with Glioblastoma; NCT02375841) completed surveys after a clinical encounter with their oncologist revealing GBM progression. Psychometrically validated measures assessed parameters of IU and religiousness. IU was compared between participants with at least a moderate or high degree of religiousness (vs. not) using Fishers-exact test. RESULTS Twenty-four adult patients (median age 57) completed surveys. Fifteen (63%) identified their illness as terminal. Six patients (25%) correctly identified their life expectancy (months), eight patients predicted life expectancy of years (33%) and ten (42%) did not know or answer. Eleven (46%) reported being moderately or very religious, while nine (38%) were slightly or not at all religious. There was significantly less frequent awareness of terminal illness amongst patients identifying as religious, spiritual, or as feeling God’s presence (all p &amp;lt; 0.05). There was significantly less frequent IU amongst patients identifying as spiritual or believing in miracles (both p &amp;lt; 0.05). CONCLUSION IU is infrequent in recurrent GBM and is significantly less frequent in patients endorsing religiousness and spirituality. Strategies to improve IU, broadly and in alignment with religious and spiritual beliefs, are warranted.
TMET-21. PROTON MAGNETIC RESONANCE SPECTROSCOPY (1H MRS) FOR THE DIAGNOSIS OF AGGRESSIVE MENINGIOMAS WITH RECURRENCE POTENTIAL
Authors: Omkar Ijare, David S Baskin, Suzanne Powell, Kumar Pichumani
Journal: Neuro-Oncology (2023)

Abstract In our previous study, we have observed elevated steady state levels of both alanine and glutamine in surgically resected tissue specimens from atypical meningioma (grade-II) patients compared to the benign (grade-I) meningioma patients. We have shown that meningioma cells utilize glutamine for the biosynthesis of alanine and other amino acids which may help in the cellular proliferation. While the role of elevated alanine in meningiomas is not well understood, this metabolite may serve as a metabolic marker for the diagnosis of aggressive meningiomas which may recur in the future. Here, we present a case of a large meningioma (7 cm x 4 cm x 8 cm) in a male patient (age: 68 years) who was diagnosed with an anterior cranial fossa, dural based extra-axial enhancing mass with the sinonasal extension compatible with a meningioma. The patient underwent multiple surgeries for the resection of the original tumor mass. Tumor tissue was collected from 2 regions: Nasal cavity and deeper tumor. Surgical pathology classified the tumor as a grade-I meningioma with MIB-1 index of ~10%. However, 1H MRS analysis of the tumor specimen showed elevated levels of alanine (Nasal cavity = 9.57 mM/g, tissue; Deep tumor = 5.50 mM/g, tissue), which are greater than the alanine levels reported for grade-II meningiomas (4.23 ± 1.92 mM). The elevated levels of alanine detected by 1H MRS suggested aggressive behavior of the tumor. After about 11 months, the repeat MRI examination showed tumor recurrence, and the patient underwent surgery again for the resection of the recurrent tumor. Surgical pathology of the recurrent tumor classified the tumor as a grade-I meningioma with increased proliferation rate (MIB-1 index of 10-12%). In conclusion, 1H MRS has potential to predict aggressive behavior of meningiomas and alanine can be used as a molecular marker for the differential diagnosis of meningiomas.